Ribonucleotide reductase (RNR) is the enzyme responsible for the reductive conversion of ribonucleotides to deoxyribonucleotides. This conversion is the rate determining step in the synthesis of deoxyribonucleic acid (DNA), an essential principle for the growth and replication of eucaryotic cells and procaryotic cells including virions. During the past few years, increasing attention has been given to searching for inhibitors of RNR with the aim of developing new therapeutic agents for controlling cell growth and replication. For example, B. van't Riet et al., J. Med. Chem., 22, 589 (1979) have described a series of benzohydroxamic acids which inhibited mammalian RNR and exhibited antineoplastic activity. P. Gaudreau et al., J. Biol. Chem., 262, 12413 (1987) described a group of peptides which selectively inhibited herpes simplex virus RNR, noting that the peptides were important tools to study the inhibition of herpes viral replication; see also R. Friedinger et al., U.S. Pat. No. 4,814,432, issued Mar. 21, 1989, describing a series of herpes simplex RNR inhibiting peptides. T. Spector et al., Proc. Natl. Acad. Sci. USA 86, 1051 (1989), described a hydrazone derivative as a potent inhibitor of herpes simplex RNR and that a combination of the derivative with acyclovir produced synergistic therapy for the topical treatment of HSV-infected animals. W. J. Dobrogosz and S. E. Lindgren, PCT patent application W088/08452, published Nov. 3, 1988, have reported the isolation of an antibiotic (reuterin) with RNR inhibiting properties which was active against certain bacteria, yeast and protozoa.
Notwithstanding the attention given the RNR inhibitors, only one such inhibitor has achieved the status as being available to the physician as a therapeutic agent, namely the antineoplastic agent hydroxyurea. Hence, there is a need for RNR inhibitors with improved activity and specificity.
The present application discloses a new group of peptides which specifically inhibit bacterial RNR. This attribute, together with a relative lack of toxicity, renders the peptides useful as antibacterial agents.